Role of arginase in allergic airway inflammation

精氨酸酶在过敏性气道炎症中的作用

• 批准号: 6688452
• 负责人: Marc E. Rothenberg
• 金额: $ 37.25万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-12-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6688452
• 关键词: Role; arginase; allergic; airway; inflammation

DESCRIPTION (provided by applicant): Using DNA microarray analysis, we were struck by the upregulation of specific genes involved in arginine metabolism during induction of experimental asthma. In particular, the genes for the arginine transporter (cationic amino acid transporter [CAT]2) and arginase I and II were strongly induced. In situ mRNA hybridization revealed strong expression of arginase I primarily in myeloid cells (macrophages) associated with inflammatory sites in the lung. In further preliminary in-vivo experiments, lung arginase I was shown to be markedly induced by IL-4 and IL-13 in a signal-transducer-and-activator-of-transcription [STAT]6 dependent manner. Interestingly, the products of arginase, polyamines and proline, regulate cell growth and connective tissue remodeling, respectively, two processes involved in the pathophysiology of asthma. Indeed, preliminary studies demonstrated increased levels of putrescine in the asthmatic lung, and inhibition of polyamine production with difluoromethylornithine (DFMO) blocked a specific pathological feature associated with experimental asthma. The main hypothesis of this grant application is that metabolism of arginine via arginase I has an important role in the pathophysiology of allergic airway responses. We propose three aims designed to dissect the regulation, expression, and relevance of arginase I in allergic airway inflammation. In Aim I, we will study the regulation of lung arginase I expression. In Aim II, we will study the functional consequences of arginase-mediated downstream pathways on the outcome of experimental asthma. In Aim III, we propose a series of translational studies aimed at examining the expression of arginase I in human lung tissue. The proposed experiments will dissect critical properties of arginine metabolism via arginase in allergic lung responses in mice and man. The pathway examined has not been previously studied in relationship to asthma, providing innovation to the proposal. It is anticipated that the proposed studies will shed new light on the pathogenesis of experimental asthma and provide a rationale for possible novel therapeutic and diagnostic interventions in asthma.

描述（由申请人提供）：使用DNA微阵列分析，在诱导实验性哮喘的过程中，参与精氨酸代谢的特定基因的上调使我们震惊。 特别是，强烈诱导了精氨酸转运蛋白（阳离子氨基酸转运蛋白[CAT] 2）和精氨酸酶I和II的基因。 原位mRNA杂交揭示了精氨酸酶I的强烈表达，主要在髓样细胞（巨噬细胞）中与肺中的炎症部位相关。 在进一步的初步体内实验中，肺精氨酸酶I被IL-4和IL-13显着诱导，在信号转移器和转录剂转录[Stat] 6依赖性方式中。 有趣的是，精氨酸酶，多胺和脯氨酸的产物分别调节细胞生长和结缔组织重塑，分别参与哮喘病理生理学的两个过程。 实际上，初步研究表明，哮喘肺中腐败水平的升高，以及用差异甲基氨酸（DFMO）抑制多胺产生的抑制作用，阻止了与实验性哮喘相关的特定病理特征。 该赠款应用的主要假设是精氨酸通过精氨酸酶的代谢在过敏性气道反应的病理生理学中具有重要作用。我们提出的三个目的旨在剖析精氨酸酶I在过敏性气道炎症中的调节，表达和相关性。 在目标I中，我们将研究肺精氨酸酶I表达的调节。 在AIM II中，我们将研究精氨酸酶介导的下游途径对实验哮喘结果的功能后果。 在AIM III中，我们提出了一系列旨在检查精氨酸I在人肺组织中的表达的翻译研究。 提出的实验将通过精氨酸酶在小鼠和人的过敏性肺反应中剖析精氨酸代谢的关键特性。 先前尚未与哮喘关系进行研究，从而为该提案提供了创新。 预计拟议的研究将为实验性哮喘的发病机理提供新的启示，并为哮喘中可能的新型治疗和诊断干预提供了理由。